Project Summary/Abstract: Autism spectrum disorders (ASD) are a set of pervasive, highly prevalent lifelong disorders for which pharmacological interventions are not readily available. While genetic factors are likely contributors to these disorders, heritability estimates indicate strong environmental contributions. Of particular interest is the link between fetal neurodevelopment and the activation of the maternal immune system during gestation. Epidemiological reports suggest a strong association between periods of maternal immune activation and an increased risk of having a child with ASD, including immune conditions such as allergies and asthma. Unique immune cascades representative of asthma and allergy responses have been detected in amniotic fluid, newborn bloodspots and maternal mid-gestation serum samples of mothers whose child was later diagnosed with ASD. Acute exacerbations are common in pregnant asthmatic women with as many 35% suffering attacks during pregnancy. In addition, air pollution, a major exacerbating factor in allergic asthma, has been separately linked with an increased risk for ASD. However, little is known about the consequences of maternal allergic asthma (MAA) responses, air pollution, or their combined effects on fetal development. In this exploratory proposal, we will create a novel model in which to test the innovative hypothesis that the particulate matter (PM) fraction of air pollution and MAA are causally linked, and in combination lead to exacerbated ASD-relevant behaviors in offspring of PM + MAA exposed dams. The proposed studies will examine the priming effects of PM sampled from the Sacramento region in combination with MAA on ASD-relevant behaviors (Aim #1). We will test the hypothesis that the combined effects of PM + MAA exposures during gestation lead to changes in immune function and microglia activation in the fetus that disrupt neurodevelopment. The proposed studies will examine whether behavioral outcomes of PM + MAA exposures are IL-4 dependent (Aim #2). If successful, this research will validate the transformative concept that ASD is, for some, a disorder due to the direct effects of common environmental contaminants, and will identify a novel mechanism for one of the most visible public health concerns of our time.